Methamphetamine (METH) abuse has reached alarming proportions, leading numerous federal agencies including NIDA, ONDCP, and the DEA to liken it to an epidemic. The medical, legal, and societal problems associated with any drug of abuse are compounded in the case of METH because it causes persistent damage to the dopamine (DA) neuronal system. Nowhere is this more evident than in individuals with AIDS, who show heightened neurotoxicity when they also abuse METH. The only cells in brain that are productively infected with HIV are microglia. The long-term objective of this proposal is to achieve a better understanding of the mechanisms by which METH exerts neurotoxicity. We hypothesize that METH intoxication leads to microglial activation. The ensuing cross-talk between distressed DA nerve endings and activated microglia, which secrete numerous species capable of damaging neurons, creates and perpetuates a vicious cycle that culminates in DA neurotoxicity. We propose 5 specific aims to test our hypotheses: 1) determine the pharmacological characteristics of methamphetamine-induced activation of microglia; 2) determine the role of COX-2, PGE2, and DA quinones in METH toxicity; 3) determine the influence of microglial status (activated by the neurotoxic HIV TAT protein or inhibited by non-competitive NMDA antagonists) on METH toxicity; 4) determine if nicotine and ?9 -tetrahydrocannabinol (THC) protect against METH toxicity through interaction with their cognate receptors on microglia; and 5) determine how microglial activation influences DAT function by culturing mammalian cells stably expressing the DA transporter with media from activated microglia. The experimental approach to these studies will combine neurochemistry, neuropharmacology, laser scanning microscopy, use of knock-out mice, and parallel studies with cultured mouse microglia cells to evaluate microglial involvement in METH toxicity. A better understanding of the mechanisms by which METH causes persistent damage to the DA neuronal system could lead to more targeted therapies and would open newer lines of investigation into this and other neurotoxic drugs of abuse.